Weight drives caspofungin pharmacokinetic variability in overweight and obese people: fractal power signatures beyond two-thirds or three-fourths

Abstract

Echinocandins, such as caspofungin, are commonly used to treat candidemia and aspergillosis. Success rates for candidemia treatment are approximately 70%. Dose optimization may further help improve these success rates, given that the microbial effect of these agents is concentration dependent. There are conflicting data as regards the effect of weight and/or obesity on caspofungin drug concentrations. We designed a prospective study to evaluate the population pharmacokinetics of caspofungin in adults with a weight difference range of 100 kg. Caspofungin pharmacokinetics were best described using a two-compartment pharmacokinetic model. There were 18 subjects studied, of whom half were women. The central volume was typically 4.2 liters but increased by a factor of (weight/53.6)(3/4). The peripheral compartment volume was typically 2.53 liters but increased by a factor of (weight/53.6)(3/2), an unusual power law signature. Similarly, the 3/4 power law best described the relationship between weight and systemic clearance for persons weighing >66.3 kg, whereas intercompartmental clearance was best described by the 3/2 power signature. There are two implications of our findings. First, lower caspofungin area-under-the-concentration-time curves are achieved in obese persons than thinner ones. This suggests that dose optimization in heavier patients may improve clinical success rates. Second, the 3/2 exponent is unusual in fractal geometry-based scaling and warrants further study. Moreover, this suggests that use of a "floating" instead of a fixed exponent may be more useful in studies where weight is under investigation as a potential cause of pharmacokinetic variability within adult patients. (This study protocol was registered at www.clinicaltrials.gov under registration number NCT01062165.).

Figures

Fig 1

Weight distribution in people recruited into the caspofungin study. (A) The recruitment was meant to capture all extremes of weight; thus, the weight is not normally distributed. (B) Distribution of weight by gender. Weight did not differ significantly by gender based on a Mann-Whitney U-test comparison.

Fig 2

Concentrations of caspofungin achieved after administration of a single 70-mg dose of caspofungin. The line is the median concentration using naïve pooling and demonstrates a biphasic decline consistent with a two-compartment model.

Fig 3

Observed versus model predicted plots for base model.

Fig 4

Relationship between natural logarithm (ln) patient mass (kg) and ln volume (liters). (A) Central compartment; (B) peripheral compartment.

Fig 5

Relationship between natural logarithm (ln) patient mass (kg) and ln systemic clearance (A), ln intercompartmental clearance (B), and ln Kpc (elimination rate constant from the peripheral compartment to the central compartment) (C).

Fig 6

Relationship between observed peak and AUC concentrations and weight.